So far, medicine lacks an intervention that can rapidly generate anti-tumor immunity. For example, vaccines can train the immune system to selectively destroy cancer cells, however they may require months to do so--by which time tumors may become lethal. Infusions of autologous T cells targeted against tumor antigens using in vitro approaches are expensive and labor-intensive, and must be personalized for each patient in specialized cell-production facilities. We propose an alternative: the research outlined here seeks to develop an off-the- shelf reagent that can quickly program tumor-recognizing capabilities into T cells without extracting them for laboratory manipulation. Specifically, we hypothesize that circulating T cells can be programmed by gene- carrying polymeric nanoparticles (NPs) to express chimeric antigen receptors (CARs) that recognize selected antigens, enabling them to mediate rapid and vigorous rejection of tumors. We also hypothesize that co- delivering a CRISPR genome editing system to silence immune checkpoints will improve the efficacy and persistence of NP-programmed T cells. Our multidisciplinary team of immunologists, bioengineers, and geneticists has already developed a novel NP configuration that can successfully introduce leukemia-specific CAR receptor genes into circulating lymphocytes. The reprogrammed cells continue to produce these receptors for weeks, allowing them to act as a `living drug' that accumulates at the target, increases in number, serially destroys tumor cells, and ultimately differentiates into long-lived memory T cells. Our eventual goal is to provide a practical, low-cost, broadly-applicable treatment that can generate anti-tumor immunity ?on demand? for oncologists in a variety of settings. As essential steps toward achieving this goal, we propose these Specific Aims: (1) To measure how effectively NP-programmed CAR expression causes the regression of advanced cancer; (2) To determine if antigen loss and tumor escape events are reduced when NP combinations program T cells to target a spectrum of antigens; and (3) To determine if silencing negative regulators of T cell function improves their anti-tumor activity. We expect our results will provide a basis to design various gene modification systems that can generate immunity against any type of cancer. Especially, they will reduce the likelihood of antigen escape variants because patients can be treated with NP-delivered CAR genes tailored to their tumor's antigenic fingerprint. These particles could be easily adapted to program lymphocytes to express high-affinity T cell receptors specific for various viral antigens, so our results may also provide a strategy for treating infectious diseases.